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Involvement of G1/S cyclins in estrogen-independent proliferation of estrogen receptor-positive breast cancer cells

Oncogene volume 21, pages 8158–8165 (2002)Cite this article

Abstract

Estrogen receptor-mediated transcription is enhanced by overexpression of G1/S cyclins D1, E or A in the presence as well in the absence of estradiol. Excess of G1/S cyclins also prevents the inhibition of transactivation of estrogen receptor (ER) by the pure antiestrogen ICI 182780. Cyclin D1 mediates this transactivation independent of complex formation to its CDK4/6 partner. This raises the possibility that overexpression of G1/S cyclins renders growth of ER-positive breast cancer hormone-independent and resistant to treatment with antiestrogens. Transient transfection of ER-positive breast cancer cell lines T47D and MCF7 with G1/S cyclins could overcome the growth arrest induced by ICI 182780 treatment. The ability of various cyclin D1 mutants to overcome the ICI 182780 mediated growth arrest corresponded with their ability to stimulate cyclin A- and E2F- promoter based reporter activities in the presence of ICI 182780. Transfection of a mutant cyclin D1 (cyclin D1-KE) that was unable to bind CDK4 and was reported to transactivate ER in the presence of ICI 182780, could not stimulate proliferation in ICI 182780 treated cells. On the other hand, cyclin D1-LALA, which is unable to stimulate ERE transactivation, could overcome the ICI 182780 cell cycle arrest. Furthermore, transient transfection of T47D cells using cyclin D1 together with a catalytic inactive mutant of CDK4 (CDK4-DN) indicated that the observed effect is due to binding to CDK inhibitors. However, a moderate, sixfold overexpression of cyclin D1 in stably transfected MCF7 cells did not overcome the ICI 182780 mediated growth arrest. These results indicate that CDK-independent transactivation of the estrogen receptor by cyclin D1 is by itself, not sufficient to result in estradiol-independent growth of breast cancer cells, whereas a vast overexpression of G1/S cyclins is able to do so, most likely by capturing of CDK inhibitors.

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Acknowledgements

We thank Drs Agami, Bernards, Chambon, Henglein and Morgan for providing various plasmid DNA's, and Dr Agami also for critical reading of the manuscript. This work was supported by grant 97-1431 of the Dutch Cancer Society to E Bindels and a grant from l'Arc to F Lallemand.

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  1. Eric MJ Bindels & François Lallemand

    Present address: Inserm U482, Centre de Recherche St Antoine, 75571, Paris, Cedex, 12, France

  2. Eric MJ Bindels and François Lallemand: These authors contributed equally to this work

Authors and Affiliations

  1. Division of Tumour Biology, The Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam, 1066, CX, The Netherlands

    Eric MJ Bindels, François Lallemand, Astrid Balkenende, Desiree Verwoerd & Rob Michalides

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Correspondence to Rob Michalides.

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Bindels, E., Lallemand, F., Balkenende, A. et al. Involvement of G1/S cyclins in estrogen-independent proliferation of estrogen receptor-positive breast cancer cells. Oncogene 21, 8158–8165 (2002). https://doi.org/10.1038/sj.onc.1206012

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